Project Summary Despite the success of antiretroviral therapy (ART) in suppressing viral replication and preventing disease progression, HIV-1 persists in a long-lived reservoir of latently infected cells that harbor integrated proviruses which can be reactivated, resulting in the lifelong requirement of ART. Efforts to identify strategies to eradicate or induce treatment-free long-term HIV-1 remission are critical. Broadly neutralizing antibodies (bNAbs) differ from ART in that they can recruit immune effector functions through their Fc domains to accelerate clearance of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster development of host immune responses. 3BNC117 and 10-1074 are bNAbs that bind to the CD4 binding site (CD4bs) and to the base of the V3 loop in HIV-1 envelope gp-120. Both antibodies show exceptional breadth and potency in vitro, and protect against or suppress infection in animal models. When administered during early chimeric simian/human immunodeficiency virus (SHIV) infection, 3BNC117 and 10-1074 led to sustained virologic control in about half of the tested animals. This effect was due to CD8+ T cell mediated control of viremia, suggesting that the bNAbs exerted immune enhancing effects. In HIV-infected adults, three doses 3BNC117 and 10-1074 over 6 weeks maintained viral suppression for an average of 21 weeks in individuals harboring antibody-sensitive viruses, including two individuals who continued to maintain viral suppression for at least 11 months after ART discontinuation. The potential immune modulatory effects of bNAbs are dependent of the availability of antigen. Fully suppressive ART reduces the frequency of infected cells expressing envelope to levels that appear to be too low to induce immunity. In contrast, bNAb-mediated viral suppression may allow sufficient antigen expression to trigger immunologic effects, and these effects are likely to be enhanced when bNAbs are used in combination with molecules known to modulate immune responses and induce viral transcription. We propose to test these concepts using N-803, an interleukin-15 superagonist, which has immune modulatory properties, such as enhancement of antibody-dependent cell-mediated cytotoxicity, and induces HIV-1 reactivation. This project aims to conduct two clinical studies to evaluate the antiviral activity of the combination of the long-acting (?LS?) variants of 3BNC117 and 10-1074 in viremic HIV- infected individuals, and to assess the ability of this long-acting dual-bNAb combination to produce sustained viral remission when administered with the IL-15 superagonist, N-803, during ART interruption.